EP0288185A1 - Thiadiazolyl guanidines - Google Patents
Thiadiazolyl guanidines Download PDFInfo
- Publication number
- EP0288185A1 EP0288185A1 EP88303127A EP88303127A EP0288185A1 EP 0288185 A1 EP0288185 A1 EP 0288185A1 EP 88303127 A EP88303127 A EP 88303127A EP 88303127 A EP88303127 A EP 88303127A EP 0288185 A1 EP0288185 A1 EP 0288185A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- compound
- formula
- thiadiazole
- toxic salt
- unit dosage
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
- C07D285/01—Five-membered rings
- C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
- C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
- C07D285/12—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
- C07D285/01—Five-membered rings
- C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
- C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
- C07D285/12—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles
- C07D285/125—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
- C07D285/135—Nitrogen atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
Definitions
- This invention relates to thiadiazole guanidines, their non-toxic salts, processes for their preparation and pharmaceutical compositions of the derivatives or their salts.
- R is hydrogen or methyl
- the invention also includes pharmaceutical compositions comprising a compound of formula 1 or a non-toxic salt thereof together with a pharmaceutically acceptable diluent or carrier.
- non-toxic salts are those with inorganic acids such as hydrochloric acid, sulphuric acid or phosphoric acid or organic acids such as acetic, propionic, malonic, succinic, fumaric, tartaric, citric or cinnamic acid.
- the compounds of formula 1 have been shown in animal tests to exhibit potent anticonvulsant activity.
- the invention also includes the use of a compound of formula 1 or a non-toxic salt thereof for the manufacture of a medicament for the treatment of epilepsy.
- the compound of formula 1 in which R is hydrogen may be prepared from a compound of formula 2 in which X is chloro or bromo by reaction with guanidine. Conveniently the reaction is carried out using an excess (3-5 molar equivalents) of guanidine at a temperature in the range 60-140°C in an anhydrous polar solvent such as t-butanol or dioxan.
- the compounds of formula 1 in which R is alkyl C1 ⁇ 4 may be prepared from a compound of formula 2 in which X is chloro or bromo by reaction with sodium cyanamide followed by reaction of the resultant substituted cyanamide with an amine RNH2 where R is alkyl C1 ⁇ 4.
- reaction of the compound of formula 2 with sodium cyanamide is carried out in an anhydrous polar solvent such as dimethylformamide.
- Reaction of the resultant substituted cyanamide with the amine RNH2 is conveniently carried out at a temperature in the range 60- 140°C.
- the invention is illustrated by the following Examples. Melting points were determined on a Kofler hot stage apparatus or a Buchi apparatus in glass capillary tubes and are uncorrected.
- mice metrazol antagonism test in mice (MMS) (Soaje-E Mé E; Lim RKS, J Pharmac Exp Ther 1962, 138 , 224; Desmedt LKC; Niemegeers CJE; Lewi PJ; Janssen PAJ, Arzneim-Forsch (Drug Res), 1976, 26 , 1592) and the electroshock test in mice (MES) (Tulloch IF; Walter DS; Howe GM; Howe SJ, Neuropharmacology 1982, 21 , 555).
- MMS metrazol antagonism test in mice
- MES electroshock test in mice
- MES maximal electroshock seizures
- MMS maximal metrazol seizures
- compositions may be in a form suitable for oral, rectal or parenteral administration.
- Such oral compositions may be in the form of capsules, tablets, granules or liquid preparations such as elixirs, syrups or suspensions.
- Tablets contain a compound of formula 1 or a non-toxic salt thereof in admixture with excipients which are suitable for the manufacture of tablets.
- excipients may be inert diluents such as calcium phosphate, microcrystalline cellulose, lactose, sucrose or dextrose; granulating and disintegrating agents such as starch; binding agents such as starch, gelatine, polyvinylpyrrolidone or acacia; and lubricating agents such as magnesium stearate, stearic acid or talc.
- compositions in the form of capsules may contain the compound or a non-toxic salt thereof mixed with an inert solid diluent such as calcium phosphate, lactose or kaolin in a hard gelatine capsule.
- an inert solid diluent such as calcium phosphate, lactose or kaolin in a hard gelatine capsule.
- compositions for parental administration may be in the form of sterile injectable preparations such as solutions or suspensions in for example water, saline or 1,3-butane diol.
- the compositions are advantageously employed in a unit dosage form.
- the unit dosage form contains from 1 to 200mg, preferably 5 to 100mg of the compound of formula 1 or a non-toxic salt thereof.
- Parenteral unit dosage forms contain from 0.1 to 25mg of the compound of formula 1 or a non-toxic salt thereof per 1ml of the preparation.
- a mixture of one part 2-guanidino-5-[2-(trifluoromethyl)phenyl]-1,3,4-thiadiazole hydrochloride and four parts microcrystalline cellulose together with 1% of magnesium stearate is compressed into tablets.
- the tablets are of such size as to contain 5, 10, 25, 50 or 100mg of the active ingredient.
- a mixture of one part 2-guanidino-5-[2-(trifluoromethyl)phenyl]-1,3,4-thiadiazole hydrochloride and four parts spray dried lactose together with 1% magnesium stearate is filled into hard gelatine capsules.
- the capsules may conveniently contain 5, 10, 25, 50 or 100mg of the active ingredient.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Pharmacology & Pharmacy (AREA)
- Pain & Pain Management (AREA)
- Animal Behavior & Ethology (AREA)
- Biomedical Technology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Compositions Of Macromolecular Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Superconductors And Manufacturing Methods Therefor (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Thiazole And Isothizaole Compounds (AREA)
- Lubricants (AREA)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AT88303127T ATE79618T1 (de) | 1987-04-24 | 1988-04-07 | Thiadiazolguanidine. |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB878709734A GB8709734D0 (en) | 1987-04-24 | 1987-04-24 | Thiadiazole derivatives |
GB8709734 | 1987-04-24 |
Publications (2)
Publication Number | Publication Date |
---|---|
EP0288185A1 true EP0288185A1 (fr) | 1988-10-26 |
EP0288185B1 EP0288185B1 (fr) | 1992-08-19 |
Family
ID=10616289
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP88303127A Expired - Lifetime EP0288185B1 (fr) | 1987-04-24 | 1988-04-07 | Thiadiazolyl guanidines |
Country Status (20)
Country | Link |
---|---|
US (1) | US4786627A (fr) |
EP (1) | EP0288185B1 (fr) |
JP (1) | JPH07121924B2 (fr) |
KR (1) | KR960010353B1 (fr) |
AT (1) | ATE79618T1 (fr) |
AU (1) | AU598663B2 (fr) |
CA (1) | CA1320491C (fr) |
DE (1) | DE3873808T2 (fr) |
DK (1) | DK220088A (fr) |
ES (1) | ES2051839T3 (fr) |
FI (1) | FI87562C (fr) |
GB (2) | GB8709734D0 (fr) |
GR (1) | GR3005479T3 (fr) |
IE (1) | IE61690B1 (fr) |
IL (1) | IL86136A (fr) |
NO (1) | NO169899C (fr) |
NZ (1) | NZ224224A (fr) |
PH (1) | PH23111A (fr) |
PT (1) | PT87310B (fr) |
ZA (1) | ZA882657B (fr) |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH0396104A (ja) * | 1989-09-08 | 1991-04-22 | Junkosha Co Ltd | 電波レンズ |
JPH03117001A (ja) * | 1989-09-28 | 1991-05-17 | Junkosha Co Ltd | 誘電体線路 |
US5126192A (en) * | 1990-01-26 | 1992-06-30 | International Business Machines Corporation | Flame retardant, low dielectric constant microsphere filled laminate |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB1578135A (en) * | 1976-06-17 | 1980-11-05 | Reckitt & Colmann Prod Ltd | Compositions containing thiadiazole derivatives |
-
1987
- 1987-04-24 GB GB878709734A patent/GB8709734D0/en active Pending
-
1988
- 1988-04-07 EP EP88303127A patent/EP0288185B1/fr not_active Expired - Lifetime
- 1988-04-07 DE DE8888303127T patent/DE3873808T2/de not_active Expired - Fee Related
- 1988-04-07 ES ES88303127T patent/ES2051839T3/es not_active Expired - Lifetime
- 1988-04-07 AT AT88303127T patent/ATE79618T1/de not_active IP Right Cessation
- 1988-04-08 US US07/179,298 patent/US4786627A/en not_active Expired - Fee Related
- 1988-04-12 NZ NZ224224A patent/NZ224224A/en unknown
- 1988-04-13 PH PH36794A patent/PH23111A/en unknown
- 1988-04-15 ZA ZA882657A patent/ZA882657B/xx unknown
- 1988-04-15 GB GB8808955A patent/GB2204038B/en not_active Expired - Lifetime
- 1988-04-18 JP JP63095383A patent/JPH07121924B2/ja not_active Expired - Lifetime
- 1988-04-19 CA CA000564451A patent/CA1320491C/fr not_active Expired - Fee Related
- 1988-04-20 IL IL86136A patent/IL86136A/xx not_active IP Right Cessation
- 1988-04-21 NO NO881734A patent/NO169899C/no unknown
- 1988-04-21 KR KR1019880004514A patent/KR960010353B1/ko not_active IP Right Cessation
- 1988-04-22 PT PT87310A patent/PT87310B/pt not_active IP Right Cessation
- 1988-04-22 IE IE120888A patent/IE61690B1/en not_active IP Right Cessation
- 1988-04-22 DK DK220088A patent/DK220088A/da not_active Application Discontinuation
- 1988-04-22 FI FI881890A patent/FI87562C/fi not_active IP Right Cessation
- 1988-04-22 AU AU15234/88A patent/AU598663B2/en not_active Ceased
-
1992
- 1992-08-20 GR GR920401818T patent/GR3005479T3/el unknown
Non-Patent Citations (3)
Title |
---|
CHEMICAL ABSTRACTS, vol. 80, no. 19, 13th May 1974, page 410, no. 108419j, Columbus, Ohio, US; P.N. BHARGAVA et al.: "Synthesis and spectral behavior of some new substituted benzothiazolyl guanidines" & CURR. SCI. 1974, 43(2), 33-6 * |
JOURNAL OF MED. CHEM., vol. 29, no. 11, November 1986, pages 2273-2280, American Chemical Society, Washington, D.C., US; C.B. CHAPLEO et al.: "Substituted 1,3,4-thiadiazoles with anticonvulsant activity. 1. hydrazines" * |
JOURNAL OF MED. CHEM., vol. 30, no. 5, May 1987, pages 951-954, American Chemical Society, Washington, D.C., US; C.B. CHAPLEO et al.: "Substituted 1,3,4-thiadiazoles with anticonvulsant activity. 3. guanidines" * |
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